More than 40 million people worldwide are infected with HIV-1, the etiologic agent for AIDS. To date, the most effective treatments for HIV infection include combinations of drugs that inhibit the action of two essential virus-encoded enzymes, reverse transcriptase and protease. However, significant problems related to drug failure, emergence of drug-resistant variants, and treatment-related adverse consequences persist. Therefore, in the absence of effective AIDS vaccines, the range of anti-HIV drugs needs to be expanded. Human cells encode proteins that naturally suppress virus infection. One of these proteins, APOBEC3G, has been found to exhibit anti-HIV-1 activity that is neutralized by the virally encoded protein Vif. APOBEC3,G is a cytidine deaminase that induces modification or cytosines to uracil in newly synthesized minus-strand viral DNA, resulting in non-functional viruses in the absence of Vif. We have recently identified a complex series of proteins, including Cu15, Elongin B, Elongin C, and Rbx1, that enable HIV to bypass the natural defenses of human cells and replicate. Discovery of these proteins that function as an E3 ubiquitin ligase is the key to understanding how HIV-1 Vif overcomes host defenses. In this application, we propose (1) To further characterize the role of Cul5-Elongin B-Elongin C E3 ubiquitin ligase complex in HIV-1 Vif function; (2) To study the molecular interaction between components of the Cul5-Elongin B-Elongin C E3 ubiquitin ligasae complex and HIV-1 Vif; (3) To examine the role of the Cul5-Elongin B-Elongin C E3 ubiquitin ligase complex in the functions of other lentiviral Vifs. The proposed research utilizes a unique model system to study the concerted action of viral as well as cellular factors. This study should provide critical insight into the complex interplay between viral and host factors and may provide us with critical information regarding the design of effective intervention strategies for HIV. [unreadable] [unreadable]